Objective To investigate the effect of psoralen on the degeneration of human nucleus pulposus cells (HNPCs)induced by interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) and its mechanism. Methods HNPCs were cultured in vitro, and HNPCs were stimulated by 10 ng/ml IL-1β and 50 ng/ml TNF-α for 24 hours to induce degeneration. Cells were divided into control group, IL-1β+TNF-α group, psoralen (10 μmol/L, 25 μmol/L and 50 μmol/L) group, psoralen (25 μmol/L) + S-phase kinase-associated protein 2 (SKP2) interference or over-expression group, psoralen + parathyroid hormone-related protein (PTHrP)recombinant protein (100 nmol/L) group, psoralen + PTHrP recombinant protein (100 nmol/L) + silent information regulator 1 (SIRT1) activator SRT1720 (1 μmol/L) group. The apoptosis of nucleus pulposus cells was detected by flow cytometry; the levels of IL-6, MMP-3 and MMP-13 in nucleus pulposus cells were detected by ELISA; the level of reactive oxygen species (ROS)in nucleus pulposus cells was detected by the DCFDA probe method. Western blotting was used to detect the expression levels of SKP2, PTHrP, SIRT1 and extracellular matrix (ECM) related protein [type II collagen (COL II) and proteoglycan protein]. Co-immunoprecipitation (Co-IP) experiment was used to verify the binding of SKP2 and PTHrP, ubiquitination experiment was used to analyze the effect of psoralen on SKP2-mediated PTHrP ubiquitination. Results Psoralen significantly inhibited cell apoptosis,the production of IL-6, MMP-3, MMP-13 and ROS (P<0.05 or P<0.01), and promoted the expression of SKP2 and ECM-related proteins of HNPCs after IL-1β and TNF-α induction in a dose-dependent manner (P<0.05). Compared with psoralen + scramble group, the expression levels of SKP2 and ECM-related proteins were significantly reduced (P<0.05), and the apoptosis rate, the levels of IL-6, MMP-3, MMP-13 and ROS were significantly increased in psoralen + SKP2 interference group (P<0.05 or P<0.01).The results of the Co-IP experiment showed that SKP2 is directly bound to PTHrP. The results of the ubiquitination experiment showed that, compared with psoralen + empty vector group, the expression level of PTHrP protein was significantly decreased, and the expression level of SKP2 protein was significantly increased in psoralen + SKP2 over-expression group (P<0.05). Compared with psoralen group, the expression levels of SIRT1 and ECM-related proteins were significantly reduced (P<0.05), and the apoptosis rate,the levels of IL-6, MMP-3, MMP-13 and ROS were significantly increased in psoralen + PTHrP recombinant protein group (P<0.05).Compared with psoralen + PTHrP recombinant protein group, the expression level of PTHrP protein did not change significantly(P>0.05), and the expression levels of SIRT1 and ECM-related proteins were significantly increased (P<0.05), the apoptosis rate,the levels of IL-6, MMP-3, MMP-13 and ROS were significantly decreased in psoralen + PTHrP recombinant protein + SRT1720 group (P<0.05). Conclusion Psoralen can promote SKP2-mediated PTHrP ubiquitination, activate SIRT1, and alleviate NP cell apoptosis in an inflammatory environment.